Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia

The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson’s disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; ​L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with ​L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses

Análisis morfotectónico y gravimétrico en un valle intermontano de la Precordillera Central de San Juan, Argentina

En este trabajo se efectúa un análisis morfotectónico y gravimétrico de la cuenca del río Talacasto, en Precordillera Central, con énfasis en el río de La Burra. Se describen además las principales estructuras con evidencia de actividad tectónica cuaternaria. La morfología irregular de la cuenca y la diversidad de depósitos aluviales encontrados a lo largo del río de La Burra (colector principal de la cuenca) permitieron inferir que la misma se encuentra en un ambiente tectónico activo con fuertes controles litológicos y estructurales. Las principales fallas descritas se ubican en el piedemonte oriental de la Sierra de La Crucecita, y occidental de la sierra de Talacasto (30º 54?-31º S y 68º 47?-68º 55? O), unos 70 km al noroeste de San Juan, en el Departamento Ullum. Las mismas se denominaron de norte a sur: Las Crucecitas y Vertientes (en el piedemonte oriental de la sierra de La Crucecita) y el sistema de falla Talacasto occidental (piedemonte occidental de la sierra homónima). Las fallas afectan depósitos asignados al Pleistoceno tardío y Holoceno y muestran en las exposiciones naturales identificadas, rasgos típicos de ambientes compresivos y que evidencian su actividad cuaternaria. Las estructuras identificadas coinciden con el estilo estructural de tectónica de piel delgada de vergencia oriental, característico de Precordillera Central. Además, se identificó un control estructural sobre el río de La Burra, con la generación de al menos tres terrazas de erosión sobre su margen izquierda. Esta deformación se vincula con el tectonismo activo que a escala regional afectó y afecta al ámbito precordillerano. Finalmente, se identificaron las principales estructuras geológicas a partir del análisis e interpretación de las anomalías gravimétricas, empleando datos obtenidos de WGM12 (World Gravity Map, 2012), que incluye datos de gravedad terrestre y satelital derivados del modelo EGM2008. La respuesta gravimétrica del basamento que compone el área en estudio, muestra una correlación con la estructura superficial y podría estar asociada a los diferentes dominios morfotectónicos reconocidos en la región.In this work, we have made a morphometric analysis of the Talacasto river basin (Central Precordillera), with emphasis on the La Burra River. The main structures with evidence of Quaternary tectonic activity are also described. The irregular morphology of the basin and the diversity of alluvial deposits found along the La Burra River allow the authors to infer that it is in an active tectonic environment with strong lithologic and structural controls. These main structures are located in the eastern piedmont of the Sierra de la Crucecita, and western piedmont of the sierra de Talacasto (30º 54’-31º S and 68º 47’-68º 55’ W), about 70 km northwest of San Juan, in the Ullum Department. The faults located in both piedmonts are named from north to south: Las Crucecitas and Vertientes (in the eastern piedmont of the La Crucecita range) and the Western Talacasto fault system (in the western piedmont of the homonymous range). The faults affect alluvial deposits assigned to the Late Pleistocene and Holocene and show typical features of ongoing compressional Quaternary tectonic activity in the evaluated natural exposures. Faults exhibit the east-verging thin-skinned structural style typical of Central Precordillera. This deformation is related to the regional tectonics that affected and currently affects the Precordilleran region. Finally, the main geological structures were identified by the analysis and interpretation of gravimetric anomalies, employing data obtained from WGM12 (World Gravity Map 2012), which includes earth and satellite gravity data derived from the EGM2008 model. The gravimetric response of the crustal blocks that compose the study area shows a correlation with the outcropping crustal structure and could be associated to the different morphotectonic domains recognized in the region.Fil: Perucca, Laura Patricia A.. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Geología "Dr. Emiliano Aparicio". Gabinete de Neotectónica y Geomorfología; ArgentinaFil: Audemard Menessier, Franck. Fundación Venezolana de Investigaciones Sismológicas; VenezuelaFil: Alcacer Sanchez, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Rothis, Luis Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Vargas Perucca, Mariana Sofía. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Geología "Dr. Emiliano Aparicio". Gabinete de Neotectónica y Geomorfología; ArgentinaFil: Haro Sanchez, Federico Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Tejada Recabarren, Flavia Emilce. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Blanc, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Vargas, Nicolás. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Geología "Dr. Emiliano Aparicio". Gabinete de Neotectónica y Geomorfología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Lara Ferrero, Gabriela Cristina. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Geología "Dr. Emiliano Aparicio". Gabinete de Neotectónica y Geomorfología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Onorato, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; Argentin

Convulsant Doses of a Dopamine D1 Receptor Agonist Result in Erk-Dependent Increases in Zif268 and Arc/Arg3.1 Expression in Mouse Dentate Gyrus

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30–45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory

Etude des mécanismes de signalisation intracellulaire impliqués dans les dyskinésies induites par la L-DOPA dans un modèle de Parkinson chez la souris

Malgré les avancées thérapeutiques récentes, la L-DOPA reste le traitement de référence de la maladie de Parkinson (MP). Malheureusement, elle présente l inconvénient majeur de déclencher après 10 ans de traitement chez 70 à 90% des patients l apparition de mouvements anormaux involontaires qui sont souvent très handicapants. Ces mouvements anormaux sont considérés comme une maladie appelée dyskinésie induite par la L-DOPA (DIL). Il y a un besoin urgent de mieux comprendre les mécanismes de développement de ces mouvements anormaux pour les prévenir ou les réduire. Cette thèse comprend différents projets de recherche concernant l étude des mécanismes intracellulaires impliqués dans le développement des DIL dans un modèle de parkinson chez la souris. Plusieurs études montrent que le développement des DIL implique une signalisation intracellulaire aberrante induite par la L-DOPA dans le striatum dénervé de fibres dopaminergiques. En particulier, une hypersensitibilité du récepteur à la dopamine D1 liée à l augmentation de sa protéine G, Gaolf, a été retrouvée chez le modèle de rat parkinsonien ainsi que chez les patients de la MP. Dans l Article I, nous avons démontré que l augmentation de cette protéine persiste chez les souris dyskinétiques. De plus, cette augmentation est responsable de l hyperactivation de la voie de signalisation cAMP/PKA observée chez les souris dyskinétiques. Dans l Article I et II, nous avons démontré le rôle prépondérant d une autre voie de signalisation induite par la L-DOPA chez les souris dyskinétiques, la voie ERK (Extracellular signal-Regulated Kinase). Par ailleurs, nous avons étudié les profils d expression des gènes associés aux dyskinésiesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy

Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies

Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.

International audienceAlthough l-3,4-dihydroxyphenylalanine (l-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by l-DOPA-induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, l-DOPA activates DA D(1) receptor (D(1)R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D(1)R activates adenylyl-cyclase through Gα(olf), a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gα(olf) levels in hemiparkinsonian mice are correlated with LID after chronic l-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Gα(olf) (Gnal(+/-)). Despite an increase in the lesioned striatum, Gα(olf) levels remained below those of unlesioned wild-type mice. In Gnal(+/-) mice, the lesion-induced l-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal(+/+) and Gnal(+/-) mice after a 10-d l-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Gα(olf) upregulation is critical for the activation by l-DOPA of D(1)R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of l-DOPA-induced ERK activation in Gnal(+/-) mice supports its causal role in LID development

Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5.

In animal models of Parkinson's disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5

Gene Expression Analyses Identify Narp Contribution in the Development of L-DOPA-Induced Dyskinesia

International audienceIn Parkinson's disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0-6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by L-DOPA. L-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson’s disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptom